The average composite dental restoration fails within 5-7 years. The primary cause of failure is at the interface between tooth structure and the restoration, and frequently results in secondary caries. Replacement of the restoration requires the removal of the old, increased loss of tooth structure, increased cost, and a decreased prognosis for the tooth. Despite extensive advances in restorative materials, success in improving the dentin-resin interface and minimizing replacement of restorations has been limited to changes to the material itself. The ultimate goal of this proposal is to develop new methods to improve dentin matrix strength and stability, and thereby enhance the durability of dentin-resin restorations. Preliminary studies provide strong support for nature-derived agents, in particular polyphenol-rich plant extracts, which strongly enhance dentin matrix properties and positively impact the dentin-resin bonds. These agents are proposed as biomodifiers of dentin matrix. This innovative approach to the clinical challenge may open new perspectives for restorative/reparative therapies of lost tooth structure. The demonstrated increase in dentin strength appears to involve interactions between dentin organic components and a family of phytoconstituents, the oligomeric proanthocyanidins (OPCs). OPCs are broadly used as natural antioxidants and have proven to be safe in various clinical applications and in herbal dietary supplements. This multidisciplinary project will focus on the biochemistry and biomechanics involved in the multi-functional interactions between OPC and major dentin matrix components, and investigates parameters involved in the formation and sustainability of dentin- resin bonds. To this end, the main hypothesis is that multi-functional interactions between the biomodifiers and dentin matrix components enhance the dentin matrix and result in quality improvement of the dentin-resin interface. In addition, phytochemical isolation and characterization of the bioactive ingredients of OPC-rich plant extracts will lead to a better understanding of the mechanisms of interaction with the dentin matrix. Combined results will enable optimization of desirable dentin activity and standardization of an interventional material for potential clinical application. The Specific Aims are: Aim 1 - Standardization of an OPC-rich natural extract with defined dentin matrix activity by means of modern phytochemical analysis; performed in tandem with Aim 2 - Determination of the short- and long-term interactions of bioactive polyphenols/OPC with the organic dentin matrix (collagen, proteoglycans, matrix metalloproteinases), as it relates to strength and stability of the tissue. Aim 3 - Establishment of clinical applicability of a standardized interventional material using in vitro models to determine both short and long-term restorative/reparative benefits of dentin biomodification. The project represents an inter-disciplinary (dentistry, pharmacy) and innovative approach to strengthening the dentin matrix substrate for restorative procedures. The outcome has potential to produce longer-lasting composite restorations, which can ultimately improve health care and reduce health care costs.